Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

COREG CR (NDA-022012)

(CARVEDILOL PHOSPHATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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07/26/2023 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Effects on Blood Sugar

(Additions and/or revisions underlined)

Betablockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

In patients with heart failure and diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when dosing with Carvedilol Phosphate extended-release capsules is initiated, adjusted, or discontinued. Trials designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.

In a trial designed to examine the effects of immediate-release carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Clinical Studies (14.4)].

6 Adverse Reactions

6.1 Clinical Trials Experience

…

Left Ventricular Dysfunction Following Myocardial Infarction

(Additions and/or revisions underlined)

The following information describes the safety experience in left ventricular dysfunction following acute myocardial infarction with immediate-release carvedilol.

Carvedilol has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received carvedilol and 980 who received placebo. Approximately 75% of the subjects received carvedilol for at least 6 months and 53% received carvedilol for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with carvedilol and placebo, respectively.

The most common adverse events reported with carvedilol in the CAPRICORN trial were consistent with the profile of the drug in the U.S. heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in greater than or equal to 3% of the subjects and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of greater than or equal to 1% but less than or equal to 3% and more frequently with carvedilol: flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression,

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of immediate- release carvedilol tablets or Carvedilol Phosphate extended-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).)

Patients taking Carvedilol Phosphate extended-release capsules should be advised of the following:

Patients should not interrupt or discontinue using Carvedilol Phosphate extended-release capsules without a physician’s advice.
Patients with heart failure should consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
Patients may experience a drop in blood pressure when standing, resulting in dizziness and, rarely, fainting. Patients should sit or lie down when these symptoms of lowered blood pressure occur.
If experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks.
Patients should consult a physician if they experience dizziness or faintness, in case the dosage should be adjusted.
Patients should not crush or chew Carvedilol Phosphate extended-release capsules.
Patients should take Carvedilol Phosphate extended-release capsules with food.
Inform patients or caregivers that there is a risk of hypoglycemia when Coreg is given to patients who are fasting or who are vomiting. Instruct patients or caregivers how to monitor for signs of hypoglycemia [see Warnings and Precautions (5.6)].
Contact lens wearers may experience decreased lacrimation.

The other brand listed is a trademark owned by or licensed to its owner and is not owned by or licensed to Woodward Pharma Services LLC. The maker of this brand is not affiliated with and does not endorse Woodward Pharma Services LLC or its products.

Other

“COREG CR” revised to read “Carvedilol Phosphate extended-release capsules” throughout labeling

09/14/2017 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Carvedilol has been evaluated for safety in subjects with heart failure …

7 Drug Interactions

Additions and/or revisions underlined:Additions and/or revisions underlined:

Patients taking a ?-blocker and a drug that can deplete catecholamines …

… Concomitant administration of clonidine with a ?-blocker may cause hypotension and bradycardia.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; as below:

Risk Summary

Available data regarding use of COREG CR in pregnant women are insufficient to determine whether there are drug-associated risks of adverse developmental outcomes. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy. The use of beta blockers during the third trimester of pregnancy may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate. In animal reproduction studies, there was no evidence of adverse developmental outcomes at clinically relevant doses. Oral administration of carvedilol to pregnant rats during organogenesis resulted in post-implantation loss, decreased fetal body weight, and an increased frequency of delayed fetal skeletal development at maternally toxic doses that were 50 times the maximum recommended human dose (MRHD). In addition, oral administration of carvedilol to pregnant rabbits during organogenesis resulted in increased post-implantation loss at doses 25 times the MRHD.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk: Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions: Neonates of women with hypertension who are treated with beta-blockers during the third trimester of pregnancy may be at increased risk for hypotension, bradycardia, hypoglycemia, and respiratory depression. Observe newborns for symptoms of hypotension, bradycardia, hypoglycemia, and respiratory depression and manage accordingly.

Data

Animal Data: Studies performed in rats and rabbits given carvedilol during fetal organogenesis revealed increased post-implantation loss in rats at a maternally toxic dose of 300 mg per kg per day (50 times the MRHD as mg per m2) and in rabbits (in the absence of maternal toxicity) at doses of 75 mg per kg per day (25 times the MRHD as mg per m2). In the rats, there was also a decrease in fetal body weight at 300 mg per kg per day (50 times the MRHD as mg per m2) accompanied by an increased incidence of fetuses with delayed skeletal development. In rats, the no-effect level for embryo-fetal toxicity was 60 mg per kg per day (10 times the MRHD as mg per m2); in rabbits, it was 15 mg per kg per day (5 times the MRHD as mg per m2). In a pre- and post-natal development study in rats administered carvedilol from late gestation through lactation, increased embryo-lethality was observed at a maternally toxic dose of 200 mg per kg per day (approximately 32 times the MRHD as mg per m2), and pup mortality and delays in physical growth/development were observed at 60 mg per kg per day (10 times the MRHD as mg per m2) in the absence of maternal toxicity. The no-effect level was 12 mg per kg per day (2 times the MRHD as mg per m2). Carvedilol was present in fetal rat tissue.

8.2 Lactation

PLLR conversion; as below:

Risk Summary

There are no data on the presence of carvedilol in human milk, the effects on the breastfed infant, or the effects on milk production. Carvedilol is present in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for COREG CR and any potential adverse effects on the breastfed infant from COREG CR or from the underlying maternal condition.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

What should I tell my doctor before taking COREG CR?

are breastfeeding. It is not known if COREG CR passes into your breast milk. Talk with your doctor about the best way to feed your baby if you are taking COREG CR.

Tell your doctor about all of the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements …